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Neurodegenerative disorders
general principles
- -Diffuse; but not always symmetric (Parkinsonism, ALS)
- -Chronic (progressive) over many years; onset is typically insidious... occurs after long period of normal nervous system function. Latent period, degeneration is occuring without symptoms
- -Irreversible degeneration
- -No treatments that slow or reverse the progression of the disease
- -Little cellular response or tissue reaction (gliosis)
- -CSF is typically normal
- -leads to cell death (apoptosis, aggregations of nl or abnormal proteins) and loss of tissue, which can lead to atrophy
- -...
- -Some are from unstable nucleotide repeats
- -Threshold that leads to an impairment of gene function and the clinical disorder
- -anticipation (earlier onset in affected offspring)
- -Potentiation (worsening of disease in affected offspring
- -coding region repeat (Huntington's disease) tend to have neurodegenerative disorder that starts midlife; polyglutamine expansion leads to toxic gain of function
- -Noncoding regions (myotonic dystrophy and fragile X syndrome) result in decreased protein synthesis and a loss of function; typically involve multiple systems
- -...
- -Hereditary degenerative polyneuropathies
- onset and progression varry
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Alzheimer's disease
presentation, epidemiology
Gradually worsening dementia over years, with preservation of sensory and motor function
Onset: insidious, slow progression
- Presentation: Most pts begin with the basic amnesia syndrome which can progress to anomia, impairment of visuospatial skills, and executive dysfunction.
- -Neuropsychiatric features include depression, delusions, hallucinations
- -Mortality is most often due to medical illness (average is 8.5 years post onset of forgetfullness)
- -Common disorder; atypical presentations are often seen
- Epidemiology: Age is the only major risk factor
- -1% of 65 year olds; Incidence doubles every 5 years thereafter!
- -32% of 90 year olds have Alzheimer's
- *Risk factor within age groups:
- Apolipoprotein E genotype modifies the likelihood of older individual developing Alzheimer's
- -more ε4 alleles increase a persons risk; ε2 is protective
- -Head trauma, female sex, low education
- -All pts with Down's syndrome will develop Alzheimer's during 40s-50s
There is atosomal dominant Alzheimer's (early onset); but less than 1% of pts wtih Alzheimer's have this form
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Alzheimer's
pathology
- Pathology: required for dx: shows gross atrophy that is most severe in the cerebral higher cortex (especially medial temporal lobe structures important for memory)
- -Microscopic: neuronal loss, gliosis, abnormal neuritic plaques and neurofibrillary tangles
- 1. Cerebral atrophy: narrowing of gyri, enlargement of sulci
- -"hydrocephalus" ex vacuo
2. Neuronal loss and gliosis are present
- 3. Neuritic plaques: focal, spherical collections of dystrophic neuritic processes often surrounding a central core of amyloid
- -Proteins of amyloid core are Aβ40 and Aβ42- Plaques seen first in the association neocortex and later are found in the hippocampus
- 4. Neurofibrillary tangles: bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus. "flame shaped", easy to see in silver stain
- -Tangles are seen first in the entorhinal cortex, then in the hippocampus, then in the temporal and other neocortex; amygdala, basal forebrain, median raphe nuclei-tangles contain paired helical filaments-abnormally hyperphosphorylated forms of the protein tau
- -Filaments also contain the microtubule associated protein MAP2 and ubiquitin
Tangles are not specific for Alzheimer's disease
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Alzheimer's
pathophysiology
- Pathophysiology: deposition of Aβ peptides that result from the abnormal processing of the amyloid precursor protein (APP)
- -APP has an unknown function
inflammatory response to the aggregates of amyloid. may contribute to the abnormal tau phosphorylation and oxidative injury to neurons
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Alzheimer's
evaluation and treatment
- Evaluation: Dx is made on history and exam
- -neuroimaging may not show atrophy
- -some lab tests may be ordered to r/o other conditions
- -No good biomarkers
- Treatment:
- Non-pharmacologic therapy remains the mainstay of therapy
- -education, continue activity for as long as possible, outpatient care for as long as possible, stop driving
- Pharmacologic therapy: not very effective
- -Cholinesterase inhibitors - efficacy is equal
- 1. Donepezil - also approved for severe Alzheimer's (not just mild-moderate...)
- 2. Galantamine
- 3. Rivastigmine (patch available)
AEs: nausea, diarrhea
- Memantine - low affinity NMDA receptor antagonist (approved for moderate to severe Alzheimer's disease)
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Fronto-temporal lobar degenerations
Heterogeneous group of neurodegenerative disorders
Onset: 40s-50s (younger than those with Alzheimer's); chronic, progressive abnormalities of "frontal lobe syndrome"
-Some progressive behavioral disorder, or progressive aphasia
- Pick's disease: well defined form of fronto-temporal lobar degeneration
- -typically asymmetrical cortical atrophy in the frontal and anterior portions of the temporal lobe
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Parkinson's disease
idiopathic Parkinson's disease
Presentation, epidemiology, pathology
Gradually worsening motor dysfunction, often with additional autonomic, cognitive neuropsychiatric or additional abnormalities
- Presentation:
- 1. Onset: 45 to 70 years (peak in the 60s)
2. Motor dysfunction ( asymmetric) that includes hyper- (tremor) and hypokinetic (bradykinesia, akinesia, rigidity, postural instability and decreased associated movements)
- 3. Initial symptoms:
- -Tremor 70%
- -Gait disturbance 11%
- -Stiffness 10%
- -Slowness 10%
- -Muscle aches 8%
- ...
- -Depression, nervousness, other psych disturbances 4%
4. Autonomic dysfunction: constipation, seborrhea, excessive sweating, orthostatic hypotension
5. Cognitive and neuropsychiatric dysfunction and depression. Dementia may be present in ~15% of patients, but increases with age
6. REM sleep behavior disorder may occur before the motor manifestations
7. Variable course - most have significant motor disability within 10 years
- Epidemiology:
- -1% of 65 year olds; 3% of 85 year olds (not exponential like Alzheimer's)
- -Whites > Asians, blacks
- -Familial Parkinson's disease is rare
- -Almost always sporadic
- -Environmental risk factors: pesticides
- -Nicotine and caffeine may offer a very small degree of protection
- Pathology:
- -Pallor of the substantia nigra and of the locus ceruleus (locus ceruleus is in the ponto-midbrain junction; NE projection system)
- -Surviving pigmented neurons may contain Lewy bodies (eosinophilic core with clear halo)
- alpha-synuclein
*mediam raphe (5-HT projection system) also affected)
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Parkinson's disease
Pathophysiology, evaluation, and treatment
- Pathophysiology:
- 1. Loss of dopaminergic projections ..."too few movements"
- -Depression in Parkinson's disease is most likely due to degeneration of the locus ceruleus (source of noradrenergic projections) and median raphe (source of serotonergic projections).
2. Decrease in # of cells in substantia nigra; 30% or less of aged matched controls
- 3. α-synuclein appears to play a role in the neural degeneration in Parkinson's disease; major component of Lewy bodies
- -normal component of the synapse... instability or misfolding may lead to PD
4. Pt treated with graft of fetal substantia nigra... 10 years later, the graft will have Parkinson's disease
- Evaluation: Dx is based on history and exam
- -asymmetric
- -good response to DA replacement
- -no labs to support the dx; no biomarkers
- Therapy:
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management of various features (orthostatic hypotension, neurogenic bladder, constipation, drooling) - -Delerium is typically transient
- -Depression is treated in the usual manner
- -REM sleep behavior disorders are treated with meds that suppress REM sleep
- Non-pharmacologic therapy:
- -various therapy (occupational, physical...)
- -Deep brain stimulation: adjustable, reversible, 'destructive' lesion of the subthalamic nucleus
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Just as effective as Rx, but can be set at continual level (Rx tend to fluctuate in efficacy based on dose, which cycles up and down)
- Pharmacologic therapy: Purely symptomatic
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Carbidopa/levodopa +/- COMT inhibitor (entacapone) - -Dopamine agonist (ropinirole)
- -Muscarinic acetylcholine receptor antagonists (trihexyphenidyl, particularly effective for tremor)
- -amantadine (NMDA glutamate receptor antagonist ... might not be mechanism of action in treating PD)
- -monoamine oxidase B inhibitors (selegiline)
*as disease progresses, pt becomes less responsive to drugs; drugs more likely to be used in combination
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Dementia with Lewy bodies
Clinical overlap with both Alzheimer's and Parkinson's disease; pathologically is more similar to Parkinson's disease
- Pathology: Lewy bodies in the cortex (diffuse)
- -less distinct (not as eosinophilic); lack the halo
- -contain predominantly α-synuclein
Pathophysiology: unknown
- Presentation:
- -Parkinsonism, dementia, fluctuations in alertness and attention, and hallucination within the same year.
- -Second most common form of progressive dementia seen in elderly
- -Death on average 8 years post onset of symptoms
- -Tx is difficult: pts are prone to have hallucinations... balance DA therapy (too much leads to hallucination, too little leads to parkinsonism)
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Huntington's disease
Prototypical polyglutamine trinucleotide repeat expansion disorder
- Autosomal dominant gene codes for protein huntingtin. Threshold is 35 repeats
- -more repeats: earlier onset
- -Paternal transmission is associated with anticipation and potentiation.
- -function of normal gene is not known
- -Gain of toxic function... selective regions are vulnerable to this toxicity (caudate> putamen)
- Pathology:
- -Atrophy of caudate more than the putamen (apparent grossly and on neuroimaging)
- -nucleus accumbens (third part of the striatum) is preserved
- -loss of neurons, particularly of the medium spiny neurons, which give rise to direct and indirect pathways of the basal ganglia circuit
- -protein aggregates containing huntingtin are found on surviving neurons
- Clinical: 4-5 per million
- -Autosomal dominant, complete penetrance
- -Age of onset is 30s to 40s
- -gradually worsening loss of sccadic eye movements, chorea, frontal syndrome and other neuropsychiatric dysfunction that may include depression and suicide
- -clinical onset to death, ~15 years
- -earlier onset can present with hypokinetic movement disorder > chorea
- Tx: symptomatic and supportive
- -DA depeleters (tetrabenazine) to suppress choria
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Amyotrophic lateral sclerosis (ALS)
Lou Gehrig's disease
- Clinical: gradual progressive asymmetrical lower and upper motor neuron dysfunction in an older patient
- -Asymmetrical atrophy and weakness of the hands is a common presentation
- -50% die in 3 years
- -90% die within 6 years
- Epidemiology: ~1 per 100,000
- -Men > women (2:1)
- -onset is normally >45 years, incidence increases with age
- -Most is sporadic; 5 to 10% have familial form of ALS
- Pathology:
- -Anterior roots of the spinal cord and precentral gyrus appears atrophic (motor)
- -microscopically, reduction in # of anterior horn cells. reactive gliosis
- -surviving motor neurons often contain PAS-positive cytoplasmic inclusions called Bunina bodies
- -stained sections of cord show loss of myelinated axons in the lateral cortical spinal tract.
- -Muscles show neurogenic atrophy
- Pathophysiology: not known for the sporadic ALS
- -several genes identified in the familial ALS; most with autosomal dominant trait: copper-zinc superoxide dismutase (SOD1)
- Evaluation: Clinical; based on history and exam
- -EMG can confirm suspicion of widespread LMN dysfunction, though not found early in course
- -MRI, labs to rule out other causes...
- Tx: symptomatic and supportive
- -antimuscarinics for drooling
- -baclofen (GABA B agonist) for spasticity
- -dextromethorphan for Pseudobulbar affect (inappropriate response to social situation)
- -dietary fiber, fluids for constipation
- -Ventilator
- -Feeding tubes
- -Riluzole: only FDA approved drug that slows the course of ALS; extends trach-free survival by 2 to 3 months...
- -mechanism not known; AEs include nausea,,, abdominal discomfort, hepatotoxicity
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Spinal Muscular Atrophy
- Clinical: autosomal recessive
- -onset is infantile: birth, or within months
- -One in every 20,000 live births: 2nd most frequent cause of death from an autosomal recessive disorder
- -babies become weak and "floppy"; LMN disorder worsens and child typically dies before the age of one year
- Cause:
- -homozygous mutations of the survival motor neuron 1 (SMN1) gene.
- -Clinical severity is inversely related to the number of copies of SMN2, highly homologous nearby gene. Lots of SMN2 means less severe disease and later onset
- -SMN protein may be important for axonal transport, but appears to promote survival of motor neurons
- Pathology: loss of the anterior horn cells and brain stem motor neuron nerve cell bodies
- -associated reactive gliosis
- -Motor roots atrophy
- -Muscle pathology: atrophic fibers and scattered abnormally large muscle fibers
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Charcot Marie Tooth "disorder"
Group of hereditary motor and sensory degenerative polyneuropathies
- CMT type 1:
- -Autosomal dominant inheritance
- -demyelinating
- CMT1A (letter indicates mutation subtype)
- -duplication of region that codes for Peripheral myelin protein 22 (PMP22) which is expressed in compact myelin and is involved in the myelin compaction process in the PNS.
- Pathology: peripheral nerves show repetitive demyelination and remyelination with multiple onion bulbs that are most prominent distally
- -segmental demyelination can be seen
- Clinical: 1 in 2,500 individuals have CMT, majority is CMT1
- -Sx start by age 30, but progression is slow
- -symmetrical, predominantly motor, distal polyneuropathy
- -lower extremity atrophy
("stork leg" appearance) and weakness, very high arched feet, and "hammer toes" - -Peripheral nerves may be enlarged to palpation (onion bulb process)
- -Can be mild; many people with CMT never come to medical attention
-Pts live normal lifespan, treatment is supportive, dx is based on history, PE, and genetic testing to confirm
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Myotonic dystrophy
- Pathophysiology: Abnormal CTG trinucleotide repeat expansion on chromosome 19 that affects the mRNA for the "dystrophia myotonia protein kinase"
- -Most common muscular dystrophy in adults
- Normal people have <30 repeats; severe myotonic dystrophy pts can have thousands of repeats
- -Anticipation occurs
- -repeat expansion is in a non-coding region results in decreased protein synthesis and loss of function
- Clinical: multisystem disorder affecting 13.5 per 100,000 live births
- -Autosomal dominant with variable (but high) penetrance
- -Onset: any age, most often in young adults
- -progressive weakness and myotonia that often affects levator palpebrae, muscles of mastication and facial expression, sternocleidomastoid muscle
- *characteristic appearance
- -weakness is often distal
- -Myotonia
- delayed relaxation of a muscle following vigorous contraction
-frontal baldness, cataracts, gonadal atrophy, cardiomyopathy, abnormal glucose tolerance, sleep apnea, lower IQ
Tx: supportive, genetic counseling
- Pathology: Skeletal muscle shows variation in fiber size, and may have internal nuclei
- -Ring fiber - a subsarcolemmal band of cytoplasm that appears distinct from the center of the fiber
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Duchenne's muscular dystrophy
- Pathophysiology: loss of the protein dystrophin due to many different mutations
- -Dystrophin is one of the largest genes; high rate of mutation
- -Most mutations are deletions, the rest are frameshift or point
- -Cytoplasmic protein that is located adjacent to the cell membrane of the muscle: it forms (with an associated complex) a link between the contractile apparatus within the muscle cell and the connective tissue of the ECM
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role in transferring force of muscle contraction to surrounding tissue - -loss of this protein leads to degeneration of the muscle
- Pathology: variation in muscle fiber size, increased number of internal nuclei; degeneration, necrosis, phagocytosis of muscle fibers
- -regeneration also apparent (but not enough to keep up with the degeneration)
- -proliferation of endomysial connective tissue
- -muscle is replaced by fat and connective tissue
- Clinical: most common form of muscular dystrophy; 1 per 3,500 live male births
- -2/3rds are X-linked recessive, males affected, females asymptomatic carriers
- -1/3 are new mutations
- -onset:
<3 years; always by age of 6 years - -symmetrical and proximal > distal weakness; progressive
- -Pseudohypertrophy of calf muscle (initial hypertrophy of muscle, subsequently replaced with fat)
- -death occurs between adolescence and mid-20s
- Evaluation/Tx: Dx is suspected by history and exam
- -CK is markedly elevated
- -Genetic testing confirms, though not all can be detected
- -muscle bx reveals an absence of dystrophin
- -Tx: supportive, genetic counseling
- -Glucocorticoids may delay progression of weakness (keep them walking), but significant adverse effects
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Drugs for ALS
classes
- Disease specific therapy: Riluzole
- Spasticity: Baclofen (GABAB receptor agonist) and Tizanidine (α2 receptor agonist)
- SKM spasms, cramps: Carbamazepine, Phenytoin
- Sialorrhea: Atropine, Botulinum toxin
- Pseudobulbar affect: Dextromethorphan + quinidine
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